Storing memories for the experiences of daily life requires the hippocampus. These memories shape our personalities and decisions, and are central to our identity. Given the importance of memory, it is perhaps not surprising that hippocampal dysfunction is associated with numerous psychiatric disorders, including post- traumatic stress disorder, depression and schizophrenia. A deep understanding of hippocampal function and dysfunction has great potential to contribute to the development of new and more effective treatments for these disorders. Somehow the hippocampus stores complex patterns of inputs corresponding to experiences and does so quickly enough to keep up with the continual flow of events. While this basic phenomenon is well established, it mechanism remain somewhat mysterious. We lack a clear picture of how the hippocampus interacts with the neocortex to store long lasting memories and how these memories are used to guide behavior. We have discovered that new learning, whether it is related to exploring a new place or learning a new task in a familiar place, leads to a massive and selective increase in coordinated activity during waking behavior, and in particular during network events known as sharp-wave ripples (SWRs). These SWRs frequently activate entire sequences of hippocampal neurons associated with specific behaviors and have therefore been termed replay events. In parallel, we have developed new techniques that allow us to detect and interrupt these correlated patterns of neural activity in real-time. In collaboration with Dr. Karl Deisseroth we have also combined optogenetic manipulations of targeted circuits with large scale, multielectrode recording, allowing us to perturb genetically targeted hippocampal circuits and record the results in awake, behaving animals. We will use these techniques to test our central hypothesis that awake replay of past experience during SWRs is necessary for the formation and retrieval of memories in hippocampal - neocortical circuits In particular, our aims are 1) To test the hypothesis that neural activity during awake SWRs is necessary for hippocampally-dependent memory formation and retrieval, 2) To test the hypothesis that awake replay events reactivate memory traces in the cortex and 3) To test the hypothesis that the influence of the hippocampus on the cortex is greatest during behavioral states associated with awake replay. Together these aims will provide 1) a determination of the causal role of awake SWRs in learning and hippocampal memory processing and 2) a new understanding of the propagation of mnemonic activity from the hippocampus to target structures. These findings have the potential to link elements of memory formation and retrieval to specific patterns of hippocampal neural activity and to thereby point the way toward therapies where these patterns are manipulated to relieve the symptoms of disorders associated with hippocampal dysfunction. PUBLIC HEALTH RELEVANCE: The goal of our proposal is to understand how the hippocampus contributes to memory formation and memory retrieval. Our goal is to link elements of memory formation and retrieval to specific patterns of hippocampal neural activity. Since hippocampal dysfunction manifests prominently in numerous psychiatric disorders, including PTSD, depression and schizophrenia, this understanding of hippocampal function has the potential to contribute to the development of new and more relevant research and treatments for these disorders.